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Abstract
Protein kinase monopolar spindle 1 plays an important role in spindle assembly checkpoint at the onset of mitosis. Over expression of MPS1 correlated with a wide range of human tumors makes it an attractive target for finding an effective and specific inhibitor. In this work, we performed molecular dynamics simulations of protein MPS1 itself as well as protein bound systems with the inhibitor and natural substrate based on crystal structures. The reported orally bioavailable 1 h-pyrrolo [3,2-c] pyridine inhibitors of MPS1 maintained stable binding in the catalytic site, while natural substrate ATP could not stay. Comparative study of stability and flexibility of three systems reveals position shifting of β-sheet region within the catalytic site, which indicates inhibition mechanism was through stabilizing the β-sheet region. Binding free energies calculated with MM-GB/PBSA method shows different binding affinity for inhibitor and ATP. Finally, interactions between protein and inhibitor during molecular dynamic simulations were measured and counted. Residue Gly605 and Leu654 were suggested as important hot spots for stable binding of inhibitor by molecular dynamic simulation. Our results reveal an important position shifting within catalytic site for non-inhibited proteins. Together with hot spots found by molecular dynamic simulation, the results provide important information of inhibition mechanism and will be referenced for designing novel inhibitors.
Abbreviations:
- MPS1: protein kinase monopolar spindle 1
- ATP: adenosine triphosphate
- GTP: guanosine triphosphate
- MM/PBSA: Molecular Mechanics/Poisson–Boltzmann surface area
- MM/GBSA: Molecular Mechanics/Generalized Born Surface Area
- PLK1: Polo-like Kinase 1
- PDB ID: Protein Data Bank identification
- NPT: constant number, pressure, and temperature
- DSSP: definition of secondary structure of proteins
- RMSD: root mean square deviations
- RMSF: root mean square fluctuations
- HY: hydrophobic interaction
Acknowledgment
The authors gratefully thank M. S. Huan He and Prof. Yi Liu from Wuhan university for providing us some computer servers during the revision.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was funded by Major State Basic Research Development Program of China [grant number 973 Program 2015CB553701]; Major State Special Research Project of China [grant number 2016YFA0101200]. National Natural Science Foundation of China [grant number NSFC 21778050]; Recruitment Program for Young Professionals [grant number KJ2070000027].
Supplementary material
The supplementary material for this paper is available online at https://doi.10.1080/07391102.2018.1433552.